With 34 million people currently living with HIV worldwide, developing a prophylactic HIV vaccine remains a top global health priority. A CMV-based vaccine approach recently provided striking protection from pathogenic SIV replication with ~50% of rhesus macaques protected. In these protected animals, we have observed CMV-induced, SIV-specific CD8+ T cell responses that are phenotypically and functionally distinct from CD8+ T cells engendered by any other vaccine regimen, including natural infection, studied to date. The magnitude of these CMV-induced CD8+ T cell responses correlates with the profound protection from SIV replication and, strikingly, may not be restricted by MHC-I. However, rhesus macaques exhibit remarkably complex MHC genetics, thereby obfuscating the study of these protective, CMV-induced CD8+ T cell responses. In contrast, Mauritian cynomolgus macaques (MCM), descendants from a population bottleneck event, exhibit simplified MHC genetics with only seven completely described MHC haplotypes. Therefore, MCM are the ideal model to study the genetics of CMV-induced protective immunity. To this end, we will use MCM to define the restricting MHC molecule for the CMV-induced CD8+ T cell responses. In specific aim 1, we will vaccinate MCM with CMV vectors expressing SIV proteins and determine the MHC-restriction of the CMV-induced, SIV-specific CD8+ T cell responses. In specific aim 2, we will confirm that CMV-induced CD8+ T cells protect MCM from SIV challenge and measure the ability of these T cells to suppress virus in in vitro viral suppression assays. If successful, we can use this MHC-simplified nonhuman primate to fully dissect the mechanism of CMV-induced protection against SIV and in turn inform the design of a novel, prophylactic HIV vaccine based on these novel epitopes.